OBJECTIVE To evaluate the mechanisms of growth hormone (GH) action on isolated human penile erectile tissue. Human GH (hGH) has been suggested to play a role in male reproductive function, including penile erection. Nevertheless, it still remains unclear which intracellular pathways mediate the physiological effects of GH on the human corpus cavernosum (HCC). METHODS Using the organ bath technique, the effects of GH were investigated on electrical field stimulation (EFS)-induced relaxation of isolated HCC in the absence and presence of the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine (l-NOARG, 10 microm). Effects of GH on the production of tissue cyclic guanosine monophosphate (cGMP) in the absence and presence of ODQ and l-NOARG were also elucidated using radioimmunoassay. RESULTS ODQ and l-NOARG abolished the relaxation of the tissue induced by EFS, whereas amplitudes were increased by physiological concentrations of GH (1-100 nm). The attenuation of EFS-induced amplitudes by l-NOARG but not ODQ was, in part, reversed by GH. The production of cGMP (pmol cGMP/mg protein) induced by 10 nm GH was abolished in the presence of 10 microm ODQ. In contrast, the combination of GH (10 nm) and l-NOARG (10 microm) maintained cGMP production significantly greater than baseline (0.68 +/- 0.36 vs 1.07 +/- 0.48 pmol cGMP/mg protein). CONCLUSIONS Our data provide evidence that GH may act on human HCC by an NO-independent effect on guanylyl cyclase activity and may thus explain how growth factors, such as hGH, regulate male erectile function.